Before the advent of biologics, gastroenterologists seldom saw or thought in terms of mucosal healing when treating patients with inflammatory bowel disease (IBD), said Sunanda Kane, MD, FACG, from the Mayo Clinic in Rochester, Minnesota. The goal was typically to achieve clinical remission symptoms.

Today, she said, mucosal healing is the goal, and choosing from among the many therapeutic agents for achieving endoscopic and even histological remission is “no simple task.”

“We have lots of choices now,” she said. “Steroids, whether topical or systemic, are often used, and fortunately, getting less used now that we understand the long-term effects of steroid use.” Antibiotics, aminosalicylates (5-ASAs), immunomodulators such as methotrexate and calcineurin inhibitors all continue to play roles. More recently, the advent of anti-tumor necrosis factor (TNF) therapeutics and their biosimilars, anti-integrins, anti-interleukins, and now Janus kinase inhibitors, have expanded the array of tools available.

“We now have bacteria such as FMT and modified bacteria, and the so-called ‘natural’ entities, for which there is not FDA approval but there is some intriguing evidence,” she explained.

Among the key concepts Dr Kane stressed were “therapeutic decisions should be categorized into those for induction and maintenance, with the goal of obtaining and maintaining a steroid-free remission.” She also emphasized that the control of mucosal inflammation may reduce the risk of dysplasia.” It is also important, she said, “that we screen for coexistent anxiety and depression because they are very prevalent, and when identified, provide resources to address those conditions. We know when our patients have these conditions they have worse outcomes.” Also, Dr Kane said, “we should favor topical or organ-selective treatment before systemic ones for ulcerative colitis, if possible.”

In regard to ulcerative colitis (UC), Dr Kane noted that the updated guidelines for inducing remission in moderate UC may include oral budesonide. For the outpatient with moderate to severe UC, oral steroids can “put out the fire,” but there should be an exit strategy for taking the patient off steroids.

Anti-TNF therapy is definitely appropriate, Dr Kane said, reviewing the various therapeutic agents, including anti-TNF agents as well as other biologics and small molecules as monotherapy or in combination with other agents such as thiopurines.

“I often get asked, what is the success of a patient who has failed one anti-TNF and then is put on another?” Dr Kane stated, “Actually, you may be quite pleasantly surprised to find that among patients who were placed on a third anti-TNF, who were followed out to 2 years, 63% maintained remission. So it is not unreasonable to try a third anti-TNF with a patient who has failed twice before.”

Dr Kane further emphasized that the data to date show that the effectiveness of biosimilars in both Crohn disease and ulcerative colitis is unchanged from the originator molecule

“VARSITY was a ‘game changer’ in terms of being the first head-to-head study of 2 different mechanisms of action for active ulcerative colitis.” Efficacy outcomes at week 52 showed that patients treated with vedolizumab were more likely to remain in remission than those on adalimumab. Further, patients treated with vedolizumab showed statistically significantly higher rates of endoscopic improvement than the patients treated with adalimumab. 

“It's important to remember that there was no dose escalation in this study,” Dr Kane noted. “Patients who were treated with adalimumab were treated every 2 weeks, while those on [vedolizumab] received infusions every 8 weeks. So this isn’t going mimic real life, but it is still interesting. There are now multiple ongoing head-to-head studies on different mechanisms of action.”

A study of patients who failed infliximab and were then treated with either adalimumab or vedolizumab found that the patients on adalimumab failed that therapy at a higher rate than patients receiving treatment with vedolimumab. “This indicates that if a patient fails with infliximab, perhaps it’s time to move on to another mechanism of action when treating ulcerative colitis.”

Ustenkinumab is “now the newest kid on the block for ulcerative colitis.” In the UNITI trials for Crohn disease and UNIFI trials for ulcerative colitis, ustekinumab showed effectiveness in patients naïve to and exposed to anti-TNF agents, Dr Kane explained.

“What about small molecules?” she continued, explaining that these are oral and nonimmunogenic, unlike the biologics. Tofacitinib is the first small molecule approved for IBD, specifically for UC. “It inhibits JAK-STAT pathway, has great oral bioavailability, and quick onset. It has a very short half-life but prolonged effect for those who respond to it.”

Dr Kane noted that a major study concluded there was no benefit to continuing 5-ASA therapy to those escalated to antimetabolite therapy. “The chemoprotective effect of 5-ASAs is a controversial topic we should leave for another day.”

The next major advance may be in stem cell therapy. A study conducted in Spain should that allogeneic adipose stem cell infusion significantly improved closure rates for complex fistulae. “There is a very exciting future for this work,” Dr Kane said, “but unfortunately COVID stopped the trials and work in this area in the United States.”

Promising new drugs in development include p-19 selective interleukin-23 receptors mirikizumab and risankizumab; etrasimod, a selective sphinogosine 1-phosphate receptor modulator that functions through lymphocyte trafficking; subcutaneous vedolizumab for ulcerative colitis; and trials of upadacitinib for treatment of Crohn disease and ulcerative colitis, Dr Kane said.

--Rebecca Mashaw

Kane S. Choosing among the expanding armamentarium of IBD therapies. Talk presented at: American College of Gastroenterology Clinical Meeting and Postgraduate Course. October 23, 2020. Virtual.